Friday, June 27, 2014

The very terms that we use to describe the motor symptoms of
Parkinson’s disease (PD) imply a subjective scaling of time and space:
bradykinesia (slowness of movement), tachyphemia (cluttering of speech), and
micrographica (smallness of handwriting).
Although these symptoms are stable features of the disease, a remarkable
property of PD is that under some conditions the symptoms can spontaneously
improve.

In 1965, R.S. Schwab and I. Zieper, two neurologists at the
Massachusetts General Hospital, described the case of a 62-year old male PD
patient who exhibited severe tremor and severe rigidity and was totally
dependent on his wife. His wife would
start her day by dressing him, laying out his breakfast, making his lunch, go
to work, then come back in the afternoon to make his dinner and finally get him
undressed and ready for bed. One evening
his wife had severe abdominal pain and had to be taken to the hospital for
emergency surgery. The next day she woke
worried about her husband, and was surprised when the nurse told her that he
had come to visit her. He had dressed
himself, made his own breakfast, and then took a taxi to the hospital. At the hospital his neurologist noticed him
and upon examination found that he was able to walk 50% faster than in past
examinations. “All his motor tests were
improved in spite of the presence of the same amount of rigidity and tremor
that had been present before.”

A second case was another elderly male with advanced stage PD with
severe rigidity who was confined to a wheelchair, unable to walk alone, living
on the first floor of his home in Providence, RI. A hurricane approached the city and his wife left
to get some supplies from the drugstore.
“As a result of the storm the harbor overflowed 10 feet into the
street. The patient, sitting in his
wheelchair, suddenly saw the door blown in and a wall of water entered the
house. Exactly how he did it is not
clear, but he managed to get out of his wheelchair and climbed the steps to
safety on the second floor where he was found several hours later by his wife,
the waters having subsided. She found him seated in a chair as helpless as he
was before.”

While these examples are anecdotal, there are other more
controlled instances in which the PD patients show marked improvements in their
movements. One example of this is in the
movements that are made during sleep.
Although healthy people do not move during REM sleep, people with PD sometimes
experience REM sleep behavior disorder (RBD).
Valerie Cochen De Cock and her colleagues studied movements made during
sleep by PD patients and reported that the movements were “surprisingly fast,
ample, coordinated and symmetrical, without obvious signs of
parkinsonism”. They found one patient
singing a song with a “strong and sonorous voice, a wide smile on his face” (he
used to sing before his PD), another “declaiming political speeches with a loud
voice” (he used to give speeches at the town council), another “shouting and
getting hold of a heavy oak table and throwing it across the room”, and another
“fighting with an invisible foil, with great agility” (apparently to save his
lady-love from an attacking knight).

The mechanisms with which the brain of a Parkinsonian patient produces
these feats remain a complete mystery.
But these observations do hint that latent in the PD brain is the
ability to make fairly normal movements.
Yet, the movements are apparently unavailable for expression except under
extraordinary circumstances. Why?

Neuroeconomics
of movements

Pietro Mazzoni, Anna Hristova, and +John Krakauer studied this
question by asking PD patients and healthy controls to reach with their
dominant (and more affected) arm to a target.
Visual feedback for the hand was removed at reach onset, and at the end
of each reach the volunteers were given feedback with regard to the speed and
accuracy of their movement. Crucially, the
trial had to be repeated if the speed was outside the requested range. The authors found that for a given reach
velocity, the endpoint accuracy of the movements made by the PD patients was
similar to controls. This again
illustrated the latent abilities of the patients. However, the patients required many more
attempts in order to produce a reach that was as fast as the requested
speed. That is, the patients were
capable of producing movements of normal speed and accuracy, but it took them more
trials to become motivated to make the fast movements. The authors proposed that under normal
conditions, the patients seem to lack the “motor motivation” that healthy
people possessed in generating their movements.

I have suggested that one way to view this result is to consider the possibility that in
the brain, each movement is a balance between two factors: the reward that one
expects to acquire at the end of the movement, and the effort (or motor cost)
that will be spent in generating that movement (Shadmehr et al., Journal of Neuroscience, 2010).
The reward that we expect to acquire represents the subjective value of
the movement. For example, if you see a
dear friend, the subjective value for the steps that you are about to take toward
your friend are higher than if you are walking to greet someone that you may
not be so fond of. As a result, you will
walk faster toward the dear friend. (I
have often thought that to examine how my brain currently values people in my
life, I should measure the speed at which I walk toward them.)

Indeed, humans and other animals tend to move faster toward things
that they value more. This was first
illustrated by Okihide Hikosaka and his colleagues in saccadic eye movements of
monkeys. In these experiments, thirsty monkeys
were trained to move their eyes to a location in exchange for a reward
(juice). In some blocks of trials, the
juice volume was a little larger, and in some blocks the volume was a little
smaller. The peak velocity of the
saccadic eye movements in blocks in which there was more juice at stake was
larger. That is, the monkey’s eye
movements were faster when the subjective value of the movement was higher.

In the real world we do not make saccadic eye movements in exchange for juice. Rather, we move our eyes to place
the part of the visual scene that we are interested in examining on our
fovea. Do we make faster saccades to
things that we value more? In humans,
this idea was first illustrated by my former student +Minnan Xu-Wilson. She asked people to make a saccadic eye
movement to spots of light, but after the saccade was completed she ‘rewarded’
them by showing them a picture of a face, an object, or simply a noisy picture. She found that saccades that were made in
anticipation of viewing a face were faster.

These experiments illustrate that one of the factors that
influences the speed by which we move, that is the vigor of our movements, is
the subjective value of the reward that we expect to attain at the end of the
movement. The higher this expected
value, the faster the movement.

The second factor is the subjective cost of the effort that is
required to make the movement. If the
subjective value of the reward associated with two potential movements is the
same, people pick the movement that requires less effort.

Now suppose that we have to move a given distance. How does the brain decide on the speed of the
movement? The faster the speed with
which we move to cover that distance, the greater force we have to
produce. If effort is related to force
(perhaps because of metabolic cost of generating force), then the subjective cost
of effort will be higher for the faster movements as compared to the slower
movements that cover the same distance.
So if we move slower, we will produce smaller forces with our muscles
and have a lower subjective cost of effort.

However, the slow movement will bring us to our goal later. Time discounts reward. That is, it is better to arrive at a valuable
state sooner rather than later. So the
subjective value of the movement drops if we arrive later at the destination,
making it better to move fast so we get to our goal sooner.

In summary, the subjective cost of effort makes it better to
move slow so we produce smaller forces, but passage of time makes reward less
valuable. These two factors compete and
the movement that the brain produces appears to be one that is the best
possible given these two competing factors. That is, the speed at which we move is one
that produces the smallest possible effort (encouraging us to move slow), while
at the same time maximizing the subject value of the reward we hope to attain
(encouraging us to move fast).

Dopamine
disorders alter the neuroeconomics of movements

In Parkinson’s disease, some of the neurons in the substantia
nigra, a nucleus in the basal ganglia, gradually degenerate and die. These neurons provide dopamine to much of the
brain, and in particular the striatum, another region of the basal ganglia. Dopamine appears to play a critical role in
regulating the two factors that control movements: subjective value of reward
and subject cost of effort.

In the course of the last two decades, John Salamone and his
colleagues have been investigating the effects that loss of dopamine has on behavior
of rats. When rats are offered a choice
between pressing a lever a few times to obtain good food, vs. eating a less
preferred food for which they do not have to press levers, they choose to spend
the effort and press the lever to get the preferred food, but only if the lever pressing requires modest effort. But when a drug is injected into their basal
ganglia that acts as an antagonist to dopamine, the rats become less willing to
press the lever and forego the better food, settling for the less effortful choice. On the other hand, if a drug is injected that
enhances action of dopamine, the animal becomes more willing to press the
lever, even if it has to press it many times in order to earn the better food.

Therefore, it appears that when dopamine’s
actions are disrupted, the balance between subjective value of reward and cost
of effort shifts. Loss of dopamine shifts the balance by increasing cost of effort and decreasing value of reward, whereas increase of dopamine shifts the balance by decreasing cost of effort and increasing the subjective value of reward.

In this framework, loss
of dopamine in PD shifts the neuroeconomics of movements towards ones
that have smaller effort costs, which include movements that are slow. This
speculation would not explain why certain movements of the patients are better
during REM sleep, but does provide a framework for understanding the
paradoxically fast and able movements that they exhibit under extraordinary
circumstances: perhaps under these conditions, a greater proportion of
available dopamine is engaged, increasing the expected reward for the movement,
countering the effort costs.

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About Me

I was born in Iran and immigrated to the US at the age of 14. I was educated at Gonzaga University, University of Southern California, and finally MIT. I studied under the mentorship of Prof. Michael Arbib and Prof. Emilio Bizzi. I am currently Professor of Biomedical Engineering and Neuroscience, and the Director of the BME PhD Program at Johns Hopkins School of Medicine. I am a neuroscientist who uses mathematics to understand how the brain controls our movements.